Summary Neurodegenerative disorders including Alzheimer?s disease (AD) and frontotemporal dementia (FTD) are afflicting a large number of aging people. Mutations in the microtubule-associated protein tau (MAPT) gene that lead to microtubule disassembly and neuronal degeneration have been implicated in the pathogenesis of AD and FTD, however effective treatment for these diseases is still lacking. Emerging evidence suggests that epigenetic dysregulation, which can induce pathological alteration of gene expression, plays a key role in aging and neurodegeneration. Using postmortem tissues from AD patients and transgenic mice carrying mutant human Tau protein associated with FTD and AD, we have found that histone 3 trimethylation at lysine 4 (H3K4me3), which is linked to gene activation, is significantly elevated in the prefrontal cortex (PFC), a key cognitive region impaired in AD and FTD. More importantly, we have found that inhibiting H3K4-specific methyltransferases leads to the substantial recovery of synaptic function in PFC pyramidal neurons, and the significant improvement of memory- related behaviors in Tau AD model. Based on these intriguing results, we propose to further reveal the role of H3K4me3 in AD pathophysiology and treatment. Combined molecular, biochemical, electrophysiological, behavioral, and genomic approaches will be used to identify aberrant H3K4 methylation in AD human brains and Tau AD model (Aim 1); to examine the rescue effects of targeting H3K4-specific methyltransferases on synaptic and cognitive deficits in Tau AD model (Aim 2); to reveal molecular mechanisms underlying the therapeutic effects of targeting H3K4-specific methyltransferases in Tau AD model. Results gained from this project will help to identify a novel therapeutic strategy for AD and related neurodegenerative disorders associated with tauopathies.